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https://www.readbyqxmd.com/read/28936771/functional-investigation-of-a-grin2a-variant-associated-with-rolandic-epilepsy
#1
Xing-Xing Xu, Xiao-Rong Liu, Cui-Ying Fan, Jin-Xing Lai, Yi-Wu Shi, Wei Yang, Tao Su, Jun-Yu Xu, Jian-Hong Luo, Wei-Ping Liao
N-methyl-D-aspartate receptors (NMDARs), a subtype of glutamate-gated ion channels, play a central role in epileptogenesis. Recent studies have identified an increasing number of GRIN2A (a gene encoding the NMDAR GluN2A subunit) mutations in patients with epilepsy. Phenotypes of GRIN2A mutations include epilepsy-aphasia disorders and other epileptic encephalopathies, which pose challenges in clinical treatment. Here we identified a heterozygous GRIN2A mutation (c.1341T>A, p.N447K) from a boy with Rolandic epilepsy by whole-exome sequencing...
September 21, 2017: Neuroscience Bulletin
https://www.readbyqxmd.com/read/28926001/ketamine-differential-neurophysiological-dynamics-in-functional-networks-in-the-rat-brain
#2
A Ahnaou, H Huysmans, R Biermans, N V Manyakov, W H I M Drinkenburg
Recently, the N-methyl-d-aspartate-receptor (NMDAR) antagonist ketamine has emerged as a fast-onset mechanism to achieve antidepressant activity, whereas its psychomimetic, dissociative and amnestic effects have been well documented to pharmacologically model schizophrenia features in rodents. Sleep-wake architecture, neuronal oscillations and network connectivity are key mechanisms supporting brain plasticity and cognition, which are disrupted in mood disorders such as depression and schizophrenia. In rats, we investigated the dynamic effects of acute and chronic subcutaneous administration of ketamine (2...
September 19, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28924012/inhibition-of-il-1%C3%AE-signaling-normalizes-nmda-dependent-neurotransmission-and-reduces-seizure-susceptibility-in-a-mouse-model-of-creutzfeldt-jakob-disease
#3
Ilaria Bertani, Valentina Iori, Massimo Trusel, Mattia Maroso, Claudia Foray, Susanna Mantovani, Raffaella Tonini, Annamaria Vezzani, Roberto Chiesa
Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder caused by prion protein (PrP) misfolding, clinically recognized by cognitive and motor deficits, electroencephalographic (EEG) abnormalities and seizures. Its neurophysiological bases are not known. To assess the potential involvement of N-methyl-D-aspartate receptor (NMDAR) dysfunction, we analyzed NMDA-dependent synaptic plasticity in hippocampal slices from Tg(CJD) mice, which model a genetic form of CJD. Because PrP depletion may result in functional upregulation of NMDARs, we also analyzed PrP knockout (KO) mice...
September 18, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28919538/roles-of-n-methyl-d-aspartate-receptors-during-the-sensory-stimulation-evoked-field-potential-responses-in-mouse-cerebellar-cortical-molecular-layer
#4
Yin-Hua Xu, Guang-Jian Zhang, Jing-Tong Zhao, Chun-Ping Chu, Yu-Zi Li, De-Lai Qiu
The functions of N-methyl-d-aspartate receptors (NMDARs) in cerebellar cortex have been widely studied under in vitro condition, but their roles during the sensory stimulation-evoked responses in the cerebellar cortical molecular layer in living animals are currently unclear. We here investigated the roles of NMDARs during the air-puff stimulation on ipsilateral whisker pad-evoked field potential responses in cerebellar cortical molecular layer in urethane-anesthetized mice by electrophysiological recording and pharmacological methods...
September 14, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28890075/down-regulation-of-dorsal-striatal-%C3%AE-camkii-causes-striatum-related-cognitive-and-synaptic-disorders
#5
Qi Wang, Pengcheng Yin, Bin Yu, Zheng Zhao, Gal Richter-Levin, Lu Yu, Xiaohua Cao
Alpha calcium/calmodulin dependent protein kinase II (αCaMKII) is a serine/threonine protein kinase which is expressed abundantly in dorsal striatum and is highly involved in the corticostriatal synaptic plasticity. Nevertheless, it currently remains unclear whether and how αCaMKII plays a in the striatum-related neural disorders. To address the above issue, lentivirus-mediated short hairpin RNA (shRNA) was used to silence the expression of αCaMKII gene in the dorsal striatum of mice. As a consequence of down-regulation of dorsal striatal αCaMKII expression, we observed defective motor skill learning in accelerating rotarod and response learning in water cross maze...
September 8, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28877967/memantine-and-ketamine-differentially-alter-nmda-receptor-desensitization
#6
Nathan G Glasgow, Nadezhda V Povysheva, Andrea M Azofeifa, Jon W Johnson
Memantine and ketamine are clinically useful NMDA receptor (NMDAR) open channel blockers that inhibit NMDARs with similar potency and kinetics, but display vastly different clinical profiles. This discrepancy has been hypothesized to result from inhibition by memantine and ketamine of overlapping but distinct NMDAR subpopulations. For example, memantine but not ketamine may inhibit extrasynaptic NMDARs more effectively than synaptic NMDARs. However, the basis for preferential NMDAR inhibition depending on subcellular location has not been systematically investigated...
September 6, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28858777/trafficking-patterns-of-nmda-and-gabaa-receptors-in-a-mg-2-free-cultured-hippocampal-neuron-model-of-status-epilepticus
#7
Yang-Je Cho, Hyunjeong Kim, Won-Joo Kim, Seungsoo Chung, Young-Hwan Kim, Inja Cho, Byung In Lee, Kyoung Heo
An altered pattern of receptor trafficking is one of the pathophysiologic mechanisms of status epilepticus (SE). The gradual internalization of GABAA receptors (GABARs) occurs in both in vitro and in vivo models of SE and is thought to be a cause of decreased GABAergic inhibition. Unlike GABARs, little is known about alterations in NMDA receptor (NMDAR) trafficking during SE, even though increased activity of NMDARs is indispensable for the induction and maintenance of SE. Therefore, we aimed to simultaneously investigate the changes in the trafficking patterns of GABARs and NMDARs in an in vitro cultured hippocampal neuron model of SE...
August 28, 2017: Epilepsy Research
https://www.readbyqxmd.com/read/28825789/multifunctional-analogs-of-kynurenic-acid-for-the-treatment-of-alzheimer-s-disease-synthesis-pharmacology-and-molecular-modeling-studies
#8
Girdhar Singh Deora, Srinivas Kantham, Stephen Chan, Satish N Dighe, Suresh K Veliyath, Gawain McColl, Marie-Odile Parat, Ross P McGeary, Benjamin P Ross
We report the synthesis and pharmacological investigation of analogs of the endogenous molecule kynurenic acid (KYNA) as multifunctional agents for the treatment of Alzheimer's disease (AD). Synthesized KYNA analogs were tested for their N-methyl-d-aspartate (NMDA) receptor binding, mGluR5 binding and function, acetylcholinesterase (AChE) inhibition, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, interference with the amyloid β peptide (Aβ) fibrillation process, and protection against Aβ-induced toxicity in transgenic Caenorhabditis elegans strain GMC101 expressing full-length Aβ42...
September 8, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28821276/inflammatory-demyelination-alters-subcortical-visual-circuits
#9
Sheila Espírito Santo Araújo, Henrique Rocha Mendonça, Natalie A Wheeler, Paula Campello-Costa, Kimberle M Jacobs, Flávia C A Gomes, Michael A Fox, Babette Fuss
BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease classically associated with axonal damage and loss; more recently, however, synaptic changes have been recognized as additional contributing factors. An anatomical area commonly affected in MS is the visual pathway; yet, changes other than those associated with inflammatory demyelination of the optic nerve, i.e., optic neuritis, have not been described in detail. METHODS: Adult mice were subjected to a diet containing cuprizone to mimic certain aspects of inflammatory demyelination as seen in MS...
August 18, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28819639/antioxidant-treatment-in-male-mice-prevents-mitochondrial-and-synaptic-changes-in-an-nmda-receptor-dysfunction-model-of-schizophrenia
#10
Aarron Phensy, Christopher Driskill, Karen Lindquist, Lan Guo, Vivek Jeevakumar, Bryan Fowler, Heng Du, Sven Kroener
Glutamate theories of schizophrenia suggest that the disease is associated with a loss of NMDA receptors, specifically on GABAergic parvalbumin-expressing interneurons (PVIs), leading to changes in the excitation-inhibition balance in the prefrontal cortex (PFC). Oxidative stress contributes to the loss of PVI and the development of schizophrenia. Here, we investigated whether the glutathione precursor N-acetyl cysteine (NAC) can prevent changes in synaptic transmission at pyramidal cells and PVIs that result from developmental NMDAR blockade and how these changes are related to mitochondrial dysfunction in the PFCs of mice...
July 2017: ENeuro
https://www.readbyqxmd.com/read/28795439/g-protein-coupled-receptor-37-like-1-modulates-astrocyte-glutamate-transporters-and-neuronal-nmda-receptors-and-is-neuroprotective-in-ischemia
#11
Sarah Jolly, Narges Bazargani, Alejandra C Quiroga, Nigel P Pringle, David Attwell, William D Richardson, Huiliang Li
We show that the G protein-coupled receptor GPR37-like 1 (GPR37L1) is expressed in most astrocytes and some oligodendrocyte precursors in the mouse central nervous system. This contrasts with GPR37, which is mainly in mature oligodendrocytes. Comparison of wild type and Gpr37l1(-/-) mice showed that loss of GPR37L1 did not affect the input resistance or resting potential of astrocytes or neurons in the hippocampus. However, GPR37L1-mediated signalling inhibited astrocyte glutamate transporters and - surprisingly, given its lack of expression in neurons - reduced neuronal NMDA receptor (NMDAR) activity during prolonged activation of the receptors as occurs in ischemia...
August 10, 2017: Glia
https://www.readbyqxmd.com/read/28780732/assessment-of-the-target-engagement-and-d-serine-biomarker-profiles-of-the-d-amino-acid-oxidase-inhibitors-sodium-benzoate-and-pgm030756
#12
Eimear Howley, Michael Bestwick, Rosa Fradley, Helen Harrison, Mathew Leveridge, Kengo Okada, Charlotte Fieldhouse, Will Farnaby, Hannah Canning, Andy P Sykes, Kevin Merchant, Katherine Hazel, Catrina Kerr, Natasha Kinsella, Louise Walsh, David G Livermore, Isaac Hoffman, Jonathan Ellery, Phillip Mitchell, Toshal Patel, Mark Carlton, Matt Barnes, David J Miller
Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids...
August 5, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28772090/nmda-receptors-in-the-dorsal-hippocampal-area-are-involved-in-tramadol-state-dependent-memory-of-passive-avoidance-learning-in-mice
#13
Majid Jafari-Sabet, Hamed Mofidi, Mohammad-Sadegh Attarian-Khosroshahi
The neurobiological mechanisms of tramadol abuse underlying the cognitive function are still imprecise. Considering these, the aim of the present study was to examine the possible effects of intra-CA1 injections of NMDA, an N-methyl-D-aspartate glutamate receptor (NMDAR) agonist and DL-AP5, a competitive NMDAR antagonist, on tramadol state-dependent memory. A single-trial step-down passive avoidance task was used for the assessment of memory retrieval in adult male NMRI mice. Post-training i.p. administration of an atypical MOR agonist, tramadol (2...
August 3, 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28768770/nmda-receptors-mediate-leptin-signaling-and-regulate-potassium-channel-trafficking-in-pancreatic-%C3%AE-cells
#14
Yi Wu, Dale A Fortin, Veronica A Cochrane, Pei-Chun Chen, Show-Ling Shyng
NMDA receptors (NMDARs) are Ca(2+)-permeant, ligand-gated ion channels activated by the excitatory neurotransmitter glutamate and have well-characterized roles in the nervous system. The expression and function of NMDARs in pancreatic β-cells, by contrast, are poorly understood. Here, we report a novel function of NMDARs in β-cells. Using a combination of biochemistry, electrophysiology, and imaging techniques, we now show that NMDARs have a key role in mediating the effect of leptin to modulate β-cell electrical activity by promoting AMP-activated protein kinase (AMPK)-dependent trafficking of KATP and Kv2...
September 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28751664/afferent-specific-role-of-nmda-receptors-for-the-circuit-integration-of-hippocampal-neurogliaform-cells
#15
R Chittajallu, J C Wester, M T Craig, E Barksdale, X Q Yuan, G Akgül, C Fang, D Collins, S Hunt, K A Pelkey, C J McBain
Appropriate integration of GABAergic interneurons into nascent cortical circuits is critical for ensuring normal information processing within the brain. Network and cognitive deficits associated with neurological disorders, such as schizophrenia, that result from NMDA receptor-hypofunction have been mainly attributed to dysfunction of parvalbumin-expressing interneurons that paradoxically express low levels of synaptic NMDA receptors. Here, we reveal that throughout postnatal development, thalamic, and entorhinal cortical inputs onto hippocampal neurogliaform cells are characterized by a large NMDA receptor-mediated component...
July 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28747405/nmda-receptor-dependent-presynaptic-inhibition-at-the-calyx-of-held-synapse-of-rat-pups
#16
Tomoko Oshima-Takago, Hideki Takago
N-Methyl-d-aspartate receptors (NMDARs) play diverse roles in synaptic transmission, synaptic plasticity, neuronal development and neurological diseases. In addition to their postsynaptic expression, NMDARs are also expressed in presynaptic terminals at some central synapses, and their activation modulates transmitter release. However, the regulatory mechanisms of NMDAR-dependent synaptic transmission remain largely unknown. In the present study, we demonstrated that activation of NMDARs in a nerve terminal at a central glutamatergic synapse inhibits presynaptic Ca(2+) currents (ICa) in a GluN2C/2D subunit-dependent manner, thereby decreasing nerve-evoked excitatory postsynaptic currents...
July 2017: Open Biology
https://www.readbyqxmd.com/read/28721398/calcium-stimulated-adenylyl-cyclase-subtype-1-ac1-contributes-to-ltp-in-the-insular-cortex-of-adult-mice
#17
Manabu Yamanaka, Takanori Matsuura, Haili Pan, Min Zhuo
Long-term potentiation (LTP) of synaptic transmission in the central nervous system is a key form of cortical plasticity. The insular cortex (IC) is known to play important roles in pain perception, aversive memory and mood disorders. LTP has been recently reported in the IC, however, the signaling pathway for IC LTP remains unknown. Here, we investigated the synaptic mechanism of IC LTP. We found that IC LTP induced by the pairing protocol was N-methyl-D-aspartate receptors (NMDARs) dependent, and expressed postsynaptically, since paired-pulse ratio (PPR) was not affected...
July 2017: Heliyon
https://www.readbyqxmd.com/read/28720858/gsk-3%C3%AE-deletion-in-dentate-gyrus-excitatory-neuron-impairs-synaptic-plasticity-and-memory
#18
Enjie Liu, Ao-Ji Xie, Qiuzhi Zhou, Mengzhu Li, Shujuan Zhang, Shihong Li, Weijin Wang, Xiaochuan Wang, Qun Wang, Jian-Zhi Wang
Increasing evidence suggests that glycogen synthase kinase-3β (GSK-3β) plays a crucial role in neurodegenerative/psychiatric disorders, while pan-neural knockout of GSK-3β also shows detrimental effects. Currently, the function of GSK-3β in specific type of neurons is elusive. Here, we infused AAV-CaMKII-Cre-2A-eGFP into GSK-3β(lox/lox) mice to selectively delete the kinase in excitatory neurons of hippocampal dentate gyrus (DG), and studied the effects on cognitive/psychiatric behaviors and the molecular mechanisms...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28716964/a-glun2b-selective-nmdar-antagonist-reverses-synapse-loss-and-cognitive-impairment-produced-by-the-hiv-1-protein-tat
#19
Jonathan D Raybuck, Nicholas J Hargus, Stanley A Thayer
HIV-associated neurocognitive disorder (HAND) affects approximately half of HIV-infected patients. Loss of synaptic connections is a hallmark of many neurocognitive disorders, including HAND. The HIV-1 protein transactivator of transcription (Tat) disrupts synaptic connections both in vitro and in vivo and has been linked to impaired neurocognitive function in humans. In vitro studies have shown that ifenprodil, an antagonist selective for GluN2B-containing NMDARs, reverses synapse loss when applied after Tat...
August 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28695335/glutamatergic-system-and-mtor-signaling-pathway-participate-in-the-antidepressant-like-effect-of-inosine-in-the-tail-suspension-test
#20
Filipe Marques Gonçalves, Vivian Binder Neis, Débora Kurrle Rieger, Tanara V Peres, Mark William Lopes, Isabella A Heinrich, Ana Paula Costa, Ana Lúcia S Rodrigues, Manuella P Kaster, Rodrigo Bainy Leal
Glutamatergic system and mTOR signaling pathway have been proposed to be important targets for pharmacological treatment of major depressive disorder. Previous studies have shown that inosine, an endogenous purine, is able to exert a remarkable antidepressant-like effect in mice. Nevertheless, the role of glutamatergic system and mTOR in this effect was not previously determined. This study was designed to investigate the possible modulation of NMDA receptors (NMDAR), AMPA receptors (AMPAR) and mTOR complex 1 (mTORC1) signaling pathway in the inosine anti-immobility effect in the tail suspension test (TST) in mice...
July 10, 2017: Journal of Neural Transmission
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